Overview

Neurofibromatosis 2 (NF2) is an inherited autosomal dominant syndrome characterized by multiple schwannomas, meningiomas, and ependymomas.
[1, 2, 3, 4] The most common tumor associated with the syndrome is the vestibulocochlear (cranial nerve [CN] VIII) schwannoma, and as many as 10% of patients with this tumor have NF2. Although it shares a name with neurofibromatosis type 1 (NF1; von Recklinghausen disease), the 2 diseases are separate entities.

Contrast-enhanced MRI is used to screen for NF2 of the brain and spine.
[5, 6, 7] Contrast is important for detecting small schwannomas, particularly of the spinal nerve roots, as well as small intraparenchymal ependymomas.
[8] Newer sequences, such as high-resolution fast spin-echo (FSE) T2 cisternography and true inversion recovery, can aid evaluation of the CNs.
[9, 10, 11]

Contrast-enhanced CT scan studies or gas CT cisternography, as well as myelography, have had limited roles since the emergence of MRI, but occasionally, they must be used in patients in whom MRI is contraindicated.
[12]

Neurofibromas are rarely found in NF2, which has led some to propose that the disease be termed schwannomatosis or MISME syndrome, the acronym for the following terms
[13] :

Multiple inherited schwannomas

Meningiomas

Ependymomas

The term MISME has become used widely as a mnemonic to remember the disease.

Although a presumed case of NF2 was first described in 1882 by Wishart, the disease was not separated from von Recklinghausen disease until 1987, when it was demonstrated that the 2 disorders arose from different chromosomes. The genetic defect responsible for NF2 is a deletion of a portion of chromosome 22, the same chromosomal abnormality found in spontaneous spinal schwannomas, indicating that a single location causes Schwann cell tumor growth.
[14, 15, 16, 17]

In 1988, the National Institutes of Health released a conference statement regarding neurofibromatosis that addressed the diagnosis of NF2.
[18] The criteria that were chosen for the diagnosis of NF2 were the following, of which only 1 criterion was needed to make the diagnosis:

Baser et al studied 4 different sets of diagnostic criteria and concluded that none of them is adequate in diagnosing patients who do not have bilateral acoustic neuromas at the initial workup. The authors proposed that a single set of diagnostic criteria should be devised to supplant the 4 existing sets, although when or if this will occur is not certain.

Although CN schwannomas, except for CN VIII schwannomas, also occur spontaneously, they are relatively rare. Thus, the presentation of any patient with multiple CN schwannomas, an unusual intracranial schwannoma, or a single CN III (oculomotor), CN IV (trochlear), or CN VI (abducens) schwannoma should prompt screening for NF2. In addition, consider the diagnosis in the workup of patients with multiple extra-axial brain or spine tumors, regardless of whether they are meningiomas or schwannomas.

Limitations of techniques

As a result of its excellent contrast and multiplanar capabilities, MRI optimally depicts the number, size, location, and extent of the central nervous system (CNS) neoplasms found in NF2. However, MRI does not detect most of the ocular abnormalities associated with the disease; these are evaluated best using funduscopy. In addition, cortical and choroid plexus calcifications may be missed on MRI, particularly when using FSE techniques. These are visualized better on CT scan studies.

Gas CT cisternography, in which injected intrathecal gas is maneuvered to outline CN VIII, is more sensitive than routine CT scan studies, but it is also invasive and less sensitive than MRI.

Myelography and CT myelography can depict spinal schwannomas well, but because they cannot be used to visualize intra-axial tumors, they are only indicated when patients cannot undergo MRI.

Intervention

Radiologic intervention plays a limited role in patients with NF2. In large meningiomas, intravascular embolization can be performed to shrink the tumor before further treatment, although this has not been described specifically in patients with NF2.
[20, 21, 22]

A CN schwannoma, including a unilateral CN VIII schwannoma or meningioma in a younger patient, suggests the possibility of NF2, which should result in genetic testing and a full MRI of the brain and spine. Older patients with meningiomas or a unilateral CN VIII schwannoma should not undergo an expensive workup for NF2 because the disease usually presents before the age of 40 years. Patients older than 60 years with bilateral internal auditory canal (IAC) masses are unlikely to have NF2 if it has not been diagnosed previously. A few reports of bilateral IAC metastases exist.

NF2 is an autosomal dominant condition. Because NF2 is almost always diagnosed during the reproductive years, patients and their families should receive extensive genetic counseling following diagnosis, and their children should be screened early in life.

Radiography

Intracranial abnormalities found in neurofibromatosis type 2 (NF2) are not visible on plain radiographs, except in cases of hyperostosis from a meningioma. Widening of the neural foramina and scalloping of the posterior aspect of the vertebral bodies can be seen on plain radiographs of the spine and result from pressure erosion from the schwannomas rather than the dural ectasia that causes the bony malformations in NF1.

Scoliosis is also associated with NF2 and can be measured most accurately on plain radiographs, although CT scan studies or MRI may be necessary to evaluate some of the more subtle spinal deformities. Although NF2 is associated with scoliosis, it is an uncommon cause of scoliosis, and no study has described scoliosis as a presenting sign of NF2.

Foraminal widening and posterior vertebral scalloping is not specific for NF2. The dural ectasia of NF1, as well as some bone dysplasias, can cause scalloping of the posterior vertebral bodies similar to that seen in NF2; however, the scalloping in NF2 is a result of associated tumors. Although the scalloping from NF1 and NF2 are occasionally indistinguishable on plain radiographs, either MRI or CT scanning easily distinguishes between the two.

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Computed Tomography

CN VIII schwannomas

CN VIII schwannomas are visualized on CT scans as strongly, but heterogeneously, enhancing cerebellopontine angle masses that extend from the internal auditory canal (IAC). On precontrast imaging, these schwannomas are isodense to hypodense with respect to brain tissue and may have associated cysts or hemorrhage.

The pressure of the tumor often results in widening of the IAC and is best visualized using bone windows. Gas CT cisternography, with 0.5- to 1-mm slices, can demonstrate small tumors within the IAC that are typically missed on routine CT scanning. Small schwannomas of the other CNs are easily overlooked or not visualized because of their proximity to osseous structures and the relatively poor contrast resolution of CT scanning.

Intracranial meningiomas

Intracranial meningiomas present as enhancing extra-axial masses, often with internal calcifications and adjacent hyperostosis that are best visualized with bone windows. Adjacent white matter with decreased attenuation is commonly seen when tumors are large, likely representing edema. The persistence of this abnormality for years after the tumor has been resected suggests the likely existence of a demyelinating factor as well.

When large enough, meningiomas may exhibit mass effect on the brain parenchyma and can be aggressive at times, invading the adjacent bone. Without contrast, meningiomas may have the same attenuation as the brain, but they typically have higher attenuation values resulting from the presence of calcium and a high nuclear-to-cytoplasmic ratio. Small tumors can be missed, particularly over the calvarium and in the posterior fossa, where beam-hardening artifact is the worst.

Spinal schwannomas

Spinal schwannomas appear either as dumbbell-shaped enhancing masses extending out the neural foramina or as intradural extramedullary masses in the spinal canal. CT scans show widening of the foramina or pressure erosion on the adjacent vertebral body, and sagittal reformatted images are useful.

Spinal meningiomas

Spinal meningiomas are found as intradural extramedullary masses, usually in the thoracic spine. They are best imaged on CT myelography, although they usually show enhancement on contrast CT scans. Occasionally, meningiomas extend into the neural foramina and appear as dumbbell-shaped masses with widening of the neural foramina. In these cases, distinguishing them from schwannomas or neurofibromas is difficult.

Spinal ependymomas

Spinal ependymomas are intra-axial enhancing masses seen most frequently in the cervical cord and conus. When involving the conus or filum, an ependymoma may be pedunculated and appear as an extra-axial mass. Cervical cord ependymomas are well-marginated enhancing tumors that may exhibit associated cyst formation.

Degree of confidence

Perform CT scanning only in patients with neurofibromatosis type 2 (NF2) in whom MRI is contraindicated, because MRI provides superior tumor imaging and characterization. When CT scanning must be used, perform high-resolution techniques in the axial and coronal planes, and consider CT cisternography for detecting small tumors.

Even when visualized, the type of tumor is often difficult to identify on CT scans, because a large amount of overlap is seen in tumor appearance. CT myelography is adequate in depicting the extra-axial lesions of NF2, but it is relatively poor at detecting ependymomas. CT scanning with 3-dimensional (3-D) volumetric rendering can be useful for preoperative planning in patients with NF2 and associated scoliosis or spinal dystrophy.

Magnetic resonance image (MRI) in a 62-year-old man who presented with unilateral hearing loss. This MRI demonstrates an enhancing mass in the right internal auditory canal (IAC) that was interpreted as a probable cranial nerve VIII (CN VIII) schwannoma. Although no other abnormalities were detected, the examination was performed as a limited MRI and imaged only the internal IACs. Further screening was not indicated because the chance that this patient had NF2 is exceedingly low.

CN VIII schwannomas often have heterogeneous signals, but they are typically isointense to hypointense on T1-weighted images and hyperintense on T2-weighted images.

High-resolution, heavily T2-weighted sequences have been used to detect small CN VIII schwannomas and appear to be approximately as sensitive as contrast MRI. Using this technique, the bright cerebrospinal fluid (CSF) around CN VII and CN VIII is used as a contrast agent, and schwannomas appear as small rounded masses that efface the CSF in the canal. This technique is also useful in detecting cochlear involvement by the tumor, because the cochlear turns can normally be easily identified as curvilinear areas of increased signal.

Nonenhancing areas of necrosis are often present as the schwannomas enlarge, and associated cysts or blood products from internal hemorrhage may be present.

Other CN schwannomas have a similar MRI appearance and differ only in location, occurring along the paths of the other CNs. The multiplanar capability of MRI is particularly useful in distinguishing a CN schwannoma from a meningioma adjacent to a nerve.

Meningiomas

Meningiomas in neurofibromatosis type 2 (NF2) have the same distribution and signal characteristics as spontaneous meningiomas, occurring most frequently along the falx and over the convexities (see the images below).
[29]

Sagittal T1-weighted postcontrast image in a patient with known neurofibromatosis type 2 that demonstrates 2 midline meningiomas (arrowheads), one over the convexity and one along the vein of Galen. The enhancing mass in the medulla (arrow) most likely is an ependymoma.

Axial postcontrast T1-weighted image demonstrates a large enhancing sellar meningioma surrounding both internal carotid arteries in this case of neurofibromatosis type 2 (NF2) (black arrows). Enhancing tissue in the ethmoid air cells also represents a meningioma extending through the cribriform plate. Meningiomas in patients with NF2 can be more aggressive and invasive than spontaneous meningiomas. Note the small, round, enhancing extra-axial mass posterior to the tectum (white arrow). Although this could represent another meningioma, the shape and location suggest it is a trochlear (CN IV) schwannoma instead.

Meningiomas are extra-axial tumors and thus demonstrate cortical buckling and a CSF cleft. A confluent area of white matter with increased T1 signal and decreased T2 signal may be seen in the adjacent brain parenchyma and likely results from a combination of vasogenic edema and demyelination.

Meningiomas typically are isointense with gray matter on all sequences and, when small, can be difficult to detect without contrast. Signal intensity can vary, and almost any combination of T1 and T2 signals can be seen.

Cyst formation is uncommon, but calcification occurs frequently and can cause the tumor to appear heterogeneous.

Following gadolinium administration, intense and generally homogeneous enhancement is seen, and a dural tail of enhancing dural tissue is often found extending from the tumor's dural attachment, although this is not specific for meningioma.
[30, 31]

Meningiomas in patients with NF2 may be more aggressive than spontaneously occurring ones, and the tumor may invade the adjacent calvarium and extend into the paranasal sinuses (see the image below).

Spinal meningiomas

Spinal meningiomas are also associated with NF2 and are often multiple in number. Unlike intracranial meningiomas, the spinal type calcifies in fewer than 10% of patients (see the image below).
[32]

Sagittal T1-weighted postcontrast image of the thoracic spine demonstrates an enhancing extra-axial meningioma (arrow) anterior to the cord with a complex enhancing mass (arrowheads) that represents a conus ependymoma filling the spinal canal in the lower thoracic spine.

Spinal meningiomas are typically intradural and extra-axial but can present as dumbbell-shaped masses extending through the neural foramina. In this situation, distinction from a neurofibroma or schwannoma is difficult, although the schwannoma should be brighter on T2-weighted images.

Meningiomas are usually isointense relative to the spinal cord on all image sequences and enhance strongly following gadolinium administration. Although most spinal meningiomas have a broad dural attachment similar to their intracranial counterparts, dural tail signs are found less frequently in spinal meningiomas.

Spinal ependymomas

Spinal ependymomas found in NF2 are divided into 2 groups: those that occur in the upper cord and those that occur in the conus.

Cord tumors are well-marginated, intensely enhancing lesions, frequently associated with cyst formation and hemorrhage. Ependymomas may be isointense or hypointense relative to the spinal cord on T1-weighted images and are always bright on T2-weighted images, although a peripheral rim of decreased T2 signal has been proposed as being suggestive of ependymoma.

Conus ependymomas are more often large tumors that can fill the entire spinal canal with heterogeneous signal and enhancement. When small, the tumors may be well-marginated intra-axial lesions, but when larger, they may appear to arise from the extra-axial space.

Extradural masses

Multiple extradural masses extending through the neural foramina are found in both NF1 and NF2, although in NF2 (unlike in NF1), these tumors are usually schwannomas. The tumors often have both an intraspinal and an extraspinal component, demonstrate a classic dumbbell shape, and are typically multilevel and bilateral. Signal intensities for spinal schwannomas are the same as those for intracranial schwannomas, and strong contrast enhancement is seen. Because of the multifocality of the spinal schwannomas and an association with scoliosis, coronal MRI often is helpful.

Gadolinium-based contrast agents have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness. For more information, see Nephrogenic Fibrosing Dermopathy.

Degree of confidence

MRI is the imaging modality of choice in NF2 and is accurate in detecting even small tumors. Separation of intracranial schwannomas from meningiomas may be difficult at times but is usually of little clinical value. The evaluation of the extent, size, and number of intracranial tumors in NF2 is accomplished best by MRI because of its multiplanar capability, its contrast resolution, and the spectrum of pulse sequences, each of which adds different information.

Spinal schwannomas, meningiomas, and ependymomas are also visualized best on MRI. Usually, no other imaging modality is necessary either at the time of diagnosis or as part of a follow-up regimen. Although MRI can image osseous vertebral abnormalities associated with NF2, CT scanning visualizes them better.

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Angiography

Angiography is of limited use in NF2 because most tumors are not visualized. An exception is the "mother-in-law sign" ("arrives early and stays late") of meningioma contrast enhancement. This sign comes from recognition of meningiomas during angiography by their early contrast enhancement and delayed washout. The early contrast enhancement is caused by the enlarged feeding vessels, usually pial or meningeal arteries, and the delayed tumor staining is from lack of capillary blood-brain barriers within the tumor. Unfortunately, like many signs in radiology, this is not specific and can be seen in other hypervascular tumors.

Because ependymomas and schwannomas are not particularly vascular, they are often not visible on angiography; however, when large enough, secondary mass effect on the adjacent brain can be recognized.

Sagittal T1-weighted postcontrast image in a patient with known neurofibromatosis type 2 that demonstrates 2 midline meningiomas (arrowheads), one over the convexity and one along the vein of Galen. The enhancing mass in the medulla (arrow) most likely is an ependymoma.

Axial postcontrast T1-weighted image demonstrates a large enhancing sellar meningioma surrounding both internal carotid arteries in this case of neurofibromatosis type 2 (NF2) (black arrows). Enhancing tissue in the ethmoid air cells also represents a meningioma extending through the cribriform plate. Meningiomas in patients with NF2 can be more aggressive and invasive than spontaneous meningiomas. Note the small, round, enhancing extra-axial mass posterior to the tectum (white arrow). Although this could represent another meningioma, the shape and location suggest it is a trochlear (CN IV) schwannoma instead.

Sagittal T1-weighted postcontrast image of the thoracic spine demonstrates an enhancing extra-axial meningioma (arrow) anterior to the cord with a complex enhancing mass (arrowheads) that represents a conus ependymoma filling the spinal canal in the lower thoracic spine.

Magnetic resonance image (MRI) in a 62-year-old man who presented with unilateral hearing loss. This MRI demonstrates an enhancing mass in the right internal auditory canal (IAC) that was interpreted as a probable cranial nerve VIII (CN VIII) schwannoma. Although no other abnormalities were detected, the examination was performed as a limited MRI and imaged only the internal IACs. Further screening was not indicated because the chance that this patient had NF2 is exceedingly low.

James G Smirniotopoulos, MD Chief Editor, MedPix®, Lister Hill National Center for Biomedical Communications, US National Library of Medicine; Professorial Lecturer, Department of Radiology, George Washington University School of Medicine and Health Sciences